Ammonium salt of methyl 4,4,4-trifluoro-3-oxo-butanethioate

ABSTRACT

Ammonium salt of methyl 4,4,4-trifluoro-3-oxobutanethioate (TMTFAA).

This is a division of application Ser. No. 495,172, filed Mar. 19, 1990,now U.S. Pat. No. 5,051,512.

Methods for preparation of 2,6-bis(fluorinated methyl)-pyridinedicarboxylates and pyridine dicarbothioates are disclosed in U.S. Pat.Nos. 4,692,184 and 4,618,679 and in European Patent 135,491. Thesecompounds are useful as herbicides.

The compound methyl 4,4,4-trifluoro-3-oxobutanethioate (sometimesreferred to herein as thiomethyl trifluoroacetoacetate, or TMTFAA) ismentioned as a starting material in the preparation of such pyridinedicarbothioates in U.S. Pat. No. 4,785,129.

DESCRIPTION OF THE PRIOR ART

As used herein, the following terms have the following meanings:

Dithiopyr--2-difluoromethyl-4-(2-methylpropyl)-6-trifluoromethyl-3,5-dicarbothioicacid, S,S-dimethyl ester

DABCO--1,4-diazabicyclo-[2.2.2]-octane

DBU--1,8-diazabicyclo-[5.4.0]-undec-7-ene

ETFAA--ethyl 4,4,4-trifluoro-3-oxo-butanoate

TMTFAA--methyl 4,4,4-trifluoro-3-oxo-butanethioate

IVA--isovaleraldehyde, or 3-methyl-butanal

NMR--nuclear magnetic resonance

GLC--gas-liquid chromatography

% Assay--Weight % desired product compound

% Yield--100×mols desired product/mol initial IVA starting material.

NOTE: Where a yield is shown herein in discussing the effect of varyinga process parameter, all process variables not explicitly shown to bevaried are held constant.

As outlined in Scheme I, preparation of diethyl2-difluoromethyl-4-(2-methylpropyl)-6-trifluoromethyl-3,5-pyridinedicarbothioate is accomplished by a Hantzsch-type base catalyzedintermolecular cyclization of ethyl 4,4,4-trifluoro-3-oxo-butanoate(ethyl trifluoroacetoacetate, or ETFAA) and isovaleraldehyde to form asubstituted dihydroxypyran, followed by ammonolysis. Dehydration of theresultant dihydroxypiperidines gives a mixture of 1,4 and 3,4dihydropyridine isomers. Dehydrofluorination of the dihydropyridinesusing an organic base such as DBU or 2,6-lutidine affords good yields(80% overall) of the pyridine diethylester.

Saponification of the diester, conversion of the resulting diacid to thediacid chloride, and subsequent thioesterification yields the preferredpyridine dicarbothioate herbicide dithiopyr.

The seven-step procedure carried out according to the reactionconditions and using the solvents and reagents disclosed in the priorart affords yields of dithiopyr in the range of 60% based on thestarting IVA.

By analogy to the process of Scheme I, one might reason that a processcould be developed starting with TMTFAA rather than ETFAA which wouldprovide the desired pyridine dicarbothioate directly in four reactionsteps rather than seven while employing process conditions which are thesame as, or similar to, those shown in the prior art teachings. However,in practice using the overall reaction sequence of Scheme II andproceding by way of the pyran as an intermediate using the solvents andreagents employed in the first four steps of Scheme I, a low yield ofthe desired pyridine dicarbothioate is obtained based on the startingTMTFAA. This is shown below in the Comparative Example. ##STR1##

COMPARATIVE EXAMPLE

When TMTFAA (2 equivalents) and isovaleraldehyde (1 equivalent) werereacted in the presence of catalytic piperidine in toluene, an exothermwas observed. After stirring for 12 h at 25° C., ¹⁹ F NMR showed thepresence of the pyrans.

When the pyran-forming reaction was substantially complete (after about12 hours), NH₃ was bubbled into the toluene solution until it reachedsaturation. The resulting solution was stirred overnight at roomtemperature after which a ¹⁹ F NMR spectrum indicated the presence ofcis and trans isomers of the dihydroxypiperidine.

The toluene solution of dihydroxypiperidines was treated withconcentrated H₂ SO₄ as a dehydrating agent at low temperature asdescribed in U.S. Pat. No. 3,692,184 to form a mixture ofdihydropyridine isomers. The reaction mixture was stirred an additional2 h and then poured onto ice. After drying, the toluene solution wastreated with tributylamine at reflux to dehydrofluorinate thedihydropyridines, affording the desired product dithiopyr. The presenceof this desired product was confirmed by analysis, but the yield wasvery low (less than 20% by weight).

DESCRIPTION OF THE INVENTION

As in the Comparative Example above, the process of this invention isillustrated in detail below with reference to the preparation ofspecific pyridine dicarbothioate compounds.

To improve yield of the desired pyridine dicarbothioate compound, thefollowing process of the present invention generally employs the samereaction steps as Scheme II but minimizes solvent changes between stepsand employs reagents which are more suited to the thioester compoundsencountered as starting materials and products in the various steps.Moreover, process efficiency and economics are improved in the presentprocess through the use in some instances of reagents which need not berecovered.

The overall process outlined above for the preparation of the desiredpyridine dicarbothioate product from TMTFAA consists of three operationswhich can be carried out in a single reaction vessel without isolationof intermediate compounds. These three operations are piperidineformation, dehydration, and dehydrofluorination, and each of these isdescribed in detail below.

PIPERIDINE FORMATION

The initial operation in this process consists of a Hantzsch-typecyclization reaction which is performed preferably in a solvent which isa lower alkylnitrile. Acetonitrile and butyronitrile are particularlypreferred. In this reaction which combines Steps 1 and 2 of Scheme Iinto Step 1 of Scheme II, two molecules of TMTFAA, a molecule of IVA(isovaleraldehyde), and a molecule of ammonia combine to afford theintermediate dihydroxypiperidines. The source of the ammonia (NH₃) inthis reaction step may be anhydrous ammonia or an ammonium salt(including ammonium hydroxide) which will readily yield ammonia;ammonium hydroxide is less desirable because its use entails addition ofwater to the process, and the water thus added must be removed prior tothe dehydration step which follows.

When NH₃ is used it may optionally be added to a small portion of thetotal TMTFAA to form an ammonium salt of TMTFAA, and this salt may beadded to the balance of the TMTFAA and the IVA. It is believed that thisammonium salt of TMTFAA is formed in the process as described herein inany event, but this technique may provide certain advantages in handlingthe process reagents. The salt has the formula ##STR2## and may beisolated.

The IVA generally is the limiting reagent in this reaction, whereas inthe prior art generally the trifluoroacetoacetate ester is the limitingreagent. The most preferred method of carrying out this operation interms of cost vs. yield is the one which uses substantiallystoichiometric amounts of each of the reagents. In a particularlypreferred embodiment of this process, acetonitrile or butyronitrile ischarged to the reaction vessel in an amount by weight equal to the totalweight of the reactants along with the desired amount of TMTFAA. Gaseousammonia (NH₃) is then added subsurface at a temperature below 20° C. Thedesired amount of isovaleraldehyde is then added dropwise whilemaintaining the temperature of the reaction mixture below 20° C. Thereaction is allowed to warm to 25° C. and then heated for 4 hours at 65°C. After completion of the above reaction sequence, volatiles areremoved in vacuo at 50°-60° C. and 10 torr in preparation for thedehydration reaction. In this first operation just described, it shouldbe noted that the order of addition of reactants, the temperature, andthe catalyst are different from those of the prior art: specifically,the TMTFAA is treated with ammonia either prior to addition of thealdehyde or in the presence of the aldehyde prior to reaction of theTMTFAA and the IVA to form a pyran, at a temperature below about 30° C.and preferably below about 20° C., and without addition of piperidine asa catalyst according to the teaching of the prior art.

The effect of some of the process parameters in this step on the overallyield is shown in the following Table. In all of these runs the solventused was acetonitrile and ammonia addition was carried out below 20° C.

                  TABLE                                                           ______________________________________                                             ratio                                                                         TMTFAA    method of ammonia                                                                            Temp  Time Yield                                Run  to IVA    addition       (°C.)                                                                        (h)  (%)                                  ______________________________________                                        1    3/1       NH.sub.3 added to                                                                            50    5    71                                                  TMTFAA, followed                                                              by IVA                                                         2    2/1       NH.sub.3 added to                                                                            50    5    64                                                  TMTFAA, followed                                                              by IVA                                                         3    3/1       Ammonium acetate                                                                             60    3    67                                                  added to TMTFAA,                                                              followed by IVA                                                4    2/1       NH.sub.3 added to mix of                                                                     65    4    64                                                  TMTFAA and IVA                                                 5      2/1.2   NH.sub.3 added to mix of                                                                     65    4    60                                                  TMTFAA and IVA                                                 6    2/1       NH.sub.3 added to                                                                            50      4.5                                                                              62                                                  TMTFAA to form a                                                              salt; salt added to mix                                                       of TMTFAA and                                                                 IVA                                                            ______________________________________                                    

DEHYDRATION

The second operation of this process corresponds to Step 2 of Scheme IIand involves dehydration of the dihydroxypiperidines produced in thefirst step of the process. In this step two molecules of H₂ O areremoved from the piperidines to afford a mixture of dihydropyridineisomers. In practice this is accomplished by treating the crudedihydroxypiperidine residue from Step 1, either neat or in a solution,with a dehydrating agent. It is preferred to perform the dehydration onthe neat piperidine product (i.e., in the absence of a solvent) usinganhydrous or concentrated aqueous HCl. In a particularly preferredaspect of this process, the crude dihydroxypiperidine residue from thefirst step is mixed with 32% aqueous HCl in a ratio of about 5 to about15 mols HCl per mol of IVA used in the first step and heated to 80° C.for 1-2 hours. The mixture is cooled to 40° C., and an amount of tolueneequal in weight to the initial acetonitrile charge is added. Thetoluene/HCl mixture is stirred for 30 minutes, after which agitation isstopped and the two phases are allowed to separate. The lower aqueousacid layer is removed. A sufficient amount of aqueous base is added tothe toluene solution to obtain a stable pH in the range 8-10. Additionalruns showing the effect of the dehydration reaction temperature, HClconcentration, dehydration reaction time and molar ratio of HCl to IVAused in the first step on product yield are shown in the followingTable. All runs in this Table were performed without using an organicsolvent in this step.

    ______________________________________                                                      HCl     REAC-   MOL     FINAL                                         TEMP    CONC    TION    RATIO   PRODUCT                                 RUN   (°C.)                                                                          (%)     TIME (h)                                                                              (HCl/IVA)                                                                             YIELD (%)                               ______________________________________                                        1     70      35      3       10      62                                      2     60      *Anhy   3       15      52                                      3     70      20      5       10      48                                      4     50      35      4       10      17                                      5     60      35      3       10      62                                      6     70      32      3        5      46                                      7     70      32      2       10      52                                      8     65      32      4       10      64                                      9     80      32      2       10      62                                      ______________________________________                                         *Anhy means "anhydrous".                                                 

In an alternative embodiment of this dehydration step in which a solventis used, the preferred combination of solvent and dehydrating agent isacetic acid with PCl₃ .

It has now quite unexpectedly been found that when the novel dehydrationprocess herein is employed using either HCl to treat the neat startingmaterial or when PCl₃ is used with acetic acid as a solvent a novelcompound is produced in substantial quantities. This new compound is3,5-pyridinedicarbothioic acid,2-chloro-1,2,3,4-tetrahydro-4-(2-methylpropyl)-2,6-bis(trifluoromethyl)-,S,S-dimethyl ester, Mp 154°-155° C.

The above-described dehydration of dihydroxypiperidine thioesters usingHCl as the dehydrating agent applies also to the dehydration of thecorresponding oxyesters such as those of Scheme 1. The use of HCl as thedehydrating agent for the oxyesters results in significant operationaladvantages as compared to the sulfuric acid dehydration method foroxyesters according to the prior art teachings.

DEHYDROFLUORINATION

According to the present invention, the final step of the process ofScheme II, dehydrofluorination of the dihydropyridines prepared in theprevious step to afford the final pyridine dicarbothioate product, isaccomplished by treatment with DABCO in contrast to the prior artdehydrofluorination step which employs DBU or 2,6-lutidine as theorganic base.

In this process step, DABCO may be employed in either stoichiometric orcatalytic amounts. Because DABCO is a difunctional base, thestoichiometric DABCO method uses at least one half mol of DABCO per molof starting IVA. Use of about one mol of DABCO is preferred. Thecatalytic DABCO method, on the other hand, employs substantially lessDABCO such as about 0.01 to 0.50, and preferably about 0.05 to about0.20 mol DABCO per theoretical mol of dihydropyridines (i.e., per mol oforiginal IVA) in conjunction with an amount of an additional base whichis adequate to effect substantially complete dehydrofluorination. Theadditional base used in the process in which DABCO is employed as acatalyst is a base selected from yhe group consisting of K₂ CO₃, K₂ CO₃,triethylamine, and tributylamine. Use of a catalytic amount of DABCOthus may result in a substantial economic benefit in the process.

Whichever dehydrofluorination method is employed, it is desirable tohave some water present in the process to act as a solvent for salts(such as, for example, the hydrofluoride salt of DABCO and/or of theadditional base if one is used) which may be formed in the process.

Using DABCO in either the catalytic or stoichiometric amounts, the newcompound 3,5-pyridinedicarbothioic acid, 2-chloro-1,2,3,4-tetrahydro-4-(2-methylpropyl)-2,6-bis(trifluoromethyl)-, S,S-dimethyl ester isdehydrohalogenated to dithiopyr via the loss of HCl and HF from themolecule.

Whichever specific dehydrofluorination method is used, it is desirableto conduct this process step in the presence of an inert aproticsolvent. Such solvents include, but are not limited to, benzene,toluene, xylenes, cyclohexane, monochlorobenzene, butyronitrile, andlike solvents. Moreover, while the temperature used in this process stepis not particularly critical, it is preferred to use temperatures in therange of 50° C. to 120° C., preferably 60° C. to 80° C.

In a particularly preferred embodiment using the catalytic DABCOdehydrofluorination method, the toluene solution from Step 2 is spargedvigorously with nitrogen to minimize formation of oxidation byproducts.An aqueous solution of 40% K₂ CO₃ containing 0.6 to 1.0 mol K₂ CO₃ pertheoretical mol of dihydropyridine (or per mol/original mol IVA) islikewise degassed with nitrogen. The two solutions are combined and acatalytic amount (5 to 20 mol % based on mols of original IVA charge) ofDABCO is added as a solid. The resulting blood red solution is heated atbetween about 60° and 100° C. for about 4 hours, cooled, and the aqueouslayer is removed. The toluene layer is stripped in vacuo to afford thecrude pyridine dicarbothioate in 65-70% overall yield based on theinitial amount of IVA charged with a wt % assay in the range of 80-85%.

Using the stoichiometric DABCO dehydrofluorination method, the toluenesolution from Step 2 is sparged vigorously with nitrogen to minimizeoxidation byproducts. DABCO is an aqueous solution preferably at or nearsaturation in a ratio greater than 0.50 mol, and preferably about 1 molper theoretical mol of dihydropyridine (or 1 mol/original mol IVA) islikewise sparged with nitrogen, and the two solutions are combined. Theresulting blood red solution is heated to 70° C. for about 2 hours,cooled, and the aqueous layer drained. The toluene layer is washed withtwo portions of 1N HCl to remove residual DABCO, then stripped in vacuoto afford the crude pyridine dicarbothioate in 65-70% overall yieldbased on the initial amount of TMTFAA charged with a wt % assay in therange of 80-85%.

The following Examples 1 and 2 illustrate the process of this inventionas it is used to prepare the same specific pyridine dicarbothioatecompound dithiopyr shown in the Comparative Example presented earlier.

EXAMPLE 1

The following Example 1 illustrates the use of a catalytic amount ofDABCO in the dehydrofluorination step and concentrated HCl in thedehydration step.

A reaction flask is charged with TMTFAA (0.025 mols, 5 g) and 15 gacetonitrile and cooled to 10° C. Ammonia (0.43 g, 0.025 mols) issparged subsurface to the acetonitrile/TMTFAA solution while thetemperature is maintained below 20° C. Following the ammonia addition, amixture of TMTFAA (0.025 mols, 5 g) and IVA (0.025 mols, 2.19 g) isadded dropwise to the flask while continuing to maintain the temperaturebelow 20° C. After this addition the reaction mixture is stirred 30minutes at 20° C. or less and then heated to 65° C. for 4 hours. Whenthe reaction is complete the pressure in the reactor is slowly reducedto 10 torr to remove the acetonitrile solvent, and when the solvent hasbeen completely removed the reactor pressure is increased to atmosphericwith nitrogen. To the stripped step 1 product is added 32% HCl (29 g,0.25 mols), and the mixture is heated to 80° C. for 2 hours. Toluene (15g) is added to the reactor, the reaction is cooled to 30° C., and thephases are allowed to separate for 1 hour. Following removal of thelower aqueous layer, the pH of the toluene solution is adjusted with 30%K₂ CO₃ to within a range of 8-9. A charge of 30% K₂ CO₃ (11.36 g, 0.025mols) and DABCO (0.14 g, 0.0013 mols) is added to the reactor, which isthen heated to reflux (85° C.) for 4 hours. When the reaction iscomplete, the contents are cooled to 30° C. and the phases allowed toseparate. Following removal of the lower aqueous layer, the toluenesolvent was removed under vacuum to obtain 7.73 g of crude product withan assay of 79% of the desired compound. The overall process yield ofthe pyridine carbodithioate was 61%.

The effect of the solvent used in this step is shown in the followingTable, in which in each run the temperature was held at 85° C., the timewas 4 hours, the catalytic amount of DABCO was 6% of the initial molaramount of IVA, and the molar ratio of K₂ CO₃ to initial IVA was 1.0.

    ______________________________________                                        Run         Solvent       Yield                                               ______________________________________                                        1           Toluene       64%                                                 2           Monochlorobenzene                                                                           61%                                                 3           Butyronitrile 48%                                                 ______________________________________                                    

EXAMPLE 2

The following Example 2 shows the use of a stoichiometric amount ofDABCO for dehydrofluorination and POCl₃ for dehydration.

TMTFAA (0.025 mols, 5 g) and 15 g acetonitrile are charged to a flaskand cooled to 10° C. Ammonia (0.43 g, 0.025 mols) is sparged subsurfaceinto the solution while the temperature is maintained below 20° C.Following this NH₃ addition, a mixture of TMTFAA (0.025 mols) and IVA(0.025 mols, 2.19 g) is added dropwise to the acetonitrile solution,again maintaining the temperature below 20° C. The mixture is stirredfor 30 minutes at 25° C. or below, then heated to 65° C. for 4 hours tocomplete the reaction. Acetonitrile solvent is removed by reducingreactor pressure slowly to 10 torr and maintaining a temperature of 65°C. The reactor is returned to atmospheric pressure under a N₂ blanket,and 15 g of toluene is added followed by POCl₃ (0.03 mols). The reactionflask is heated to 70° C. and held for 1 hour then cooled to below 30°C. Water is added slowly in an amount equal in weight to the toluenecharge (15 g), maintaining the 30° C. temperature. The water layer isseparated and removed, then the pH of the toluene solution is adjustedwith 20% NaOH to within the range of 8-9, after which the aqueous layeris removed. DABCO (0.025 mols, 2.8 g) and 2.8 g water are combined,sparged with nitrogen, and added to the toluene solution which has beensparged with nitrogen. The mixture is heated to 70° C. for 2 hours, thencooled to 25°-30° C. and the aqueous layer was removed. The organiclayer is washed with two portions of 1N HCl (20 g), separated and driedover MgSO₄. The toluene is removed under vacuum to afford crude productdithiopyr. The overall yield of dithiopyr in this example is 66%.

While the process of this invention has been specifically illustrated interms of a specific pyridine dicarbothioate product, it is equallyapplicable to the preparation of other pyridine compounds. Selection ofthe aldehyde starting material will, of course, determine thesubstituent at the 4-position of the final pyridine product. Likewise itis evident that lower alkyl trifluoroacetoacetate thioesters other thanthe methylthio ester may equally well be employed. Accordingly, thescope of this invention is to be limited only in accordance with theannexed claims.

We claim:
 1. The compound ##STR3##